(Pro)renin Receptor Inhibition Reprograms Hepatic Lipid Metabolism and Protects Mice from Diet-Induced Obesity and Hepatosteatosis
Rationale: An elevated level of plasma low-density lipoprotein (LDL) is an established risk factor for cardiovascular disease. Recently, we reported that the (pro)renin receptor ([P]RR) regulates LDL metabolism in vitro via the LDL receptor (LDLR) and SORT1, independently of the renin-angiotensin system.
Objective: To investigate the physiological role of [P]RR in lipid metabolism in vivo.
Methods and Results: We used N-Acetylgalactosamine (GalNAc) modified antisense oligonucleotides (ASO) to specifically inhibit hepatic [P]RR expression in C57BL/6J mice, and studied the consequences this has on lipid metabolism. In line with our earlier report, hepatic [P]RR silencing increased plasma LDL cholesterol. Unexpectedly, this also resulted in markedly reduced plasma triglycerides in a SORT1-independent manner in C57BL/6J mice fed a normal or high fat diet. In LDLR-deficient mice, hepatic (P)RR inhibition reduced both plasma cholesterol and triglycerides, in a diet-independent manner. Mechanistically, we found that [P]RR inhibition decreased protein abundance of acetyl-CoA carboxylase (ACC) and pyruvate dehydrogenase (PDH). This alteration reprograms hepatic metabolism, leading to reduced lipid synthesis and increased fatty acid oxidation. As a result, hepatic [P]RR inhibition attenuated diet-induced obesity and hepatosteatosis.
Conclusions: Collectively, our study suggests that [P]RR plays a key role in energy homeostasis and regulation of plasma lipids by integrating hepatic glucose and lipid metabolism.
- fatty liver disease
- (pro)renin receptor
- lipids and lipoprotein metabolism
- renin angiotensin system
- Received November 18, 2017.
- Accepted December 29, 2017.